The acceptance of Rett Syndrome (RS) as a nosologic entity seems well established. Current data suggest that RS is a genetic disorder, sporadic in most instances and explained in the most parsimonious manner by an X-linked dominant mutation. Despite an all -out-effort, no consistent or convincing biochemical or pathologic marker provides diagnostic certainty. The clinical pattern suggests an arrested development based on a failure in cell differentiation or loss of a critical cell population. This process could be degenerative, but from a longitudinal perspective RS does not feature a relentless downhill course after the initial regression phase. The first study group on RS, sponsored by the Research for Rett Syndrome Foundation, in October 1990, surveyed the current understanding of RS and identified specific areas for future study. Among these was the need to focus on the development of a biological marker, particularly through molecular genetic techniques. Detailed analysis at the cellular level is needed including morphometry and receptor-ligand binding studies. A national data base should be established using existing centers and IRSA, to establish survival data and identify familial cases. Clinical trials should be carefully designed and conducted using existing models. Assuming a period of failed cell interaction or cell degeneration, a search based on known mechanisms of programmed cell death or genetically-based cell loss should be undertaken. This should include examination of excitatory amino acid receptors. Clearly, the identifi- cation or creation of an animal model would provide an important advance. It is now timely to conduct a second study group to assess progress in the intervening time and to redirect emphasis as indicated by new information. The present application seeks support to supplement available funding from the Research for Rett Foundation and the International Rett Syndrome Association.